Catalytic Hydroxycyclopropanol Ring-Opening Carbonylative Lactonization to Fused Bicyclic Lactones

Article abstract of DOI:10.1021/jacs.0c06179

A novel palladium-catalyzed ring opening carbonylative lactonization of readily available hydroxycyclopropanols was developed to efficiently synthesize tetrahydrofuran (THF) or tetrahydropyran (THP)-fused bicyclic γ-lactones, two privileged scaffolds ofte

Full text of DOI:10.1021/jacs.0c06179

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Communication
Catalytic Hydroxycyclopropanol Ring-Opening
Carbonylative Lactonization to Fused Bicyclic Lactones
XINPEI CAI, Weida Liang, Mingxin Liu, Xiating Li, and Mingji Dai
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c06179 • Publication Date (Web): 20 Jul 2020
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Page 1 of 8
Journal of the American Chemical Society
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Catalytic Hydroxycyclopropanol Ring-Opening Carbonylative Lactoniza-
tion to Fused Bicyclic Lactones
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Xinpei Cai, Weida Liang, Mingxin Liu, Xiating Li, and Mingji Dai*
Department of Chemistry and Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States
Supporting Information Placeholder
paracaseolide A inhibits phosphatase CDC25B, an
emerging and important target for anticancer drug discov-
ery; the marine spongian diterpenoid norrisolide and its
analogs demonstrated unique Golgi-modifying activity;
darwinolide is a biofilm-penetrating anti-MRSA agent.
ABSTRACT: A novel palladium-catalyzed ring opening
carbonylative lactonization of readily available hy-
droxycyclopropanols was developed to efficiently syn-
thesize tetrahydrofuran (THF) or tetrahydropyran (THP)-
fused bicyclic g-lactones, two privileged scaffolds often
found in natural products. The reaction features mild re-
action conditions, good functional group tolerability, and
scalability. Its application was demonstrated in a short to-
tal synthesis of (±)-paeonilide. The fused bicyclic g-lac-
tone products can be easily diversified to other medici-
nally important scaffolds, which further broadens the ap-
plication of this new carbonylation method.
Additionally,
the
related
cis-2,9-dioxabicy-
clo[4.3.0]nonan-8-one (a THP-fused bicyclic g-lactone,
also called cis-tetrahydro-4H-furo[2,3-b]pyran-2(3H)-
one) has been found in natural products,9 including ap-
planatumol B (1h),9a which showed activity against renal
fibrosis.
O
O
HO
O
O
H
HO
O
H
Me
O
O
O
O
OH
H
O
H
H
tBu
Me
H
Me
Me
9
Me
O
O
Me
H
HO
O
O
AcO
O
10
H
OAc
Nature has been constantly creating natural products
with novel, diverse, and complex structures. Many of
these natural products or their derivatives have been used
as medicines to treat human diseases or are lead com-
pounds for drug discovery.1 While various biosynthetic
pathways and different organisms are involved in natural
product production, privileged structural scaffolds shared
by a large number of natural products can often be iden-
tified.1c Cis-2,8-dioxabicyclo[3.3.0]octan-3-one (a THF-
fused bicyclic g-lactone, also called cis-tetrahydro[2,3-
b]furan-2(3H)-one) is one such privileged structural scaf-
fold, which has been found in over 100 natural products
from various origins (Figure 1).2 In these molecules, the
THF-fused g-lactone forges diverse connections with the
rest of the molecular structures. Part of them such as gink-
golide B (1a),3 gracilin B (1b),4 paracaseolide A (1c),5
and darwinolide (1d),6 have the bicyclic g-lactone moiety
embedded in a large polycyclic ring system. Another por-
tion of them including norrisolide (1e)7 and cheloviolene
A (1f)8 have the bicyclic g-lactone connected with a sec-
ond (poly)cyclic ring system via a C-C single bond. Why
and how nature produces such fused bicyclic skeletons
are yet to be understood. Natural products with such a bi-
cyclic g-lactone motif have demonstrated a wide range of
biological activity and possess great potential in novel
therapeutic development. For example, the ginkgolides
can act as anti-platelet-activating factors; gracilins exhibit
immunosuppressive and neuroprotective properties;
Me
Ginkgolide B (1a)
Gracilin B (1b)
Paracaseolide A (1c)
AcO
OAc
H
O
O
H
Me
O
O
H
Me
H
H
H
n
O
O
O
O
Me
THF/THP-fused
γ-lactone
O
H
Me
Me
Me Me
Darwinolide (1d)
Norrisolide (1e)
(n = 1, 2)
H
O
HO
OH
O
H
H
O
H
H
Me
O
O
H
O
O
O
O
H
O
O
OH
O
H
Me
Me
Me
HO
Applanatumol B (1h)
Cheloviolene A (1f)
Paeonilide (1g)
Figure 1. Selected natural products with a THF/THP-fused
bicyclic g-lactone
Due to their unique and challenging chemical structures
as well as their diverse biological applications, natural
products with a THF/THP-fused bicyclic g-lactone moi-
ety have been popular targets in total synthesis prac-
tices.10 Notably, the Overman group recently accom-
plished elegant total syntheses of several marine spongian
diterpenoids including cheloviolene A (1f, Figure 1) with
a THF-fused g-lactone.11 So far, most of these total syn-
theses utilized the hydroxy-acid-aldehyde (or their
masked forms) condensation reactions to construct the
desired THF/THP-fused g-lactone moiety in the target
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Journal of the American Chemical Society
molecules (eq. A-1, Figure 2A). In these processes, tedi-
Page 2 of 8
prepare THF/THP-fused g-lactones with various substitu-
tion patterns (Figure 2C). To achieve this goal, cyclopro-
panols such as 6 would be required. They can be conver-
gently assembled from readily available ester 7 and
homoallylic alcohol 8 using the cyclopropanol synthesis15
protocol developed by Cha and co-workers.16 We envi-
sioned a process involving Pd-catalyzed b-carbon elimi-
nation to generate Pd-homoenolate 9. Ideally, we hoped
for an acetal formation followed by carbonylative lactoni-
zation to convert 9 to desired fused bicyclic g-lactone 11,
presumably via an intermediate like 10. In principle, sev-
eral processes could compete with the desired one. For
instance, b-hydride elimination would decompose 9 to an
enone; the tethered secondary alcohol could attack the Pd
center and a following C-O reductive elimination would
give THF product 12. Additionally, carbonylative lactoni-
zation with the same tethered alcohol would give d-lac-
tone 14 (9®13®14). At the planning stage, we didn’t
know which pathway would dominate, but it would be
ideal to develop conditions to access 11, 12, or 14 at wish.
We were particularly attracted by the conversion of hy-
droxycyclopropanol 6 to fused lactone 11. The estab-
lished modular assembly of 6 would enable the introduc-
tion of various substitutions in product 11, especially at
the ring junction carbon where the R group resides. Mean-
while, we were hoping that the use of bishomoallylic al-
cohols may eventually result in THP-fused g-lactones.
Given the prevalence of THF/THP-fused g-lactones in bi-
ologically active natural products, this chemistry is ex-
pected to find broad application in facilitating the chemi-
cal syntheses of those natural products and their analogs.
Herein, we report such a Pd-catalyzed hydroxycyclopro-
panol ring opening carbonylative lactonization to the
aforementioned bicyclic g-lactones and its application in
a short total synthesis of (±)-paeonilide (1g) and other
medicinally important bicyclic and polycyclic scaffolds.
1
ous functional group manipulations, protections, and
deprotections are often involved, which added extra steps
to the entire synthesis. Surprisingly, synthetic methodol-
ogy development in this area is extremely barren.12 Nota-
bly, Trost and Toste developed a Pd-catalyzed asymmet-
ric nucleophilic substitution of 5-aceloxy-2-(5H)-
furanone followed by reductive intramolecular Heck re-
action to build THF-fused g-lactones,12a but this method
is limited to benzo-fused tricyclic systems (eq. A-2). The-
odorakis12b and Reiser12c independently reported elegant
activated cyclopropane rearrangements to THF-fused g-
lactones (eq. A-3). In the Reiser’s case, the activated cy-
clopropanes were generated via Rh-catalyzed enantiose-
lective cyclopropanation of furans. In general, these prior
arts are limited to 5,5-fused g-lactones and hydrogen atom
substitution at the ring junction carbons. Thus, versatile,
modular, and catalytic methods are highly desirable.
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A. Selected THF/THP-fused γ-lactone synthesis
O
OPG
O
OH
n
n
O
n
(A-1)
OR
OH
O
O
X
O
n = 1,2
hydroxy-acid-aldehyde
O
H
I
I
BocO
Pd2dba3
O
O
Pd cat.
R
R
O
O
(A-2)
R
O
O
HCOOH
OH
O
H
H
chiral ligand
high ee
Trost & Toste, 1999
H
H
R
CO2Et
CO2Et
N2
R
R
O
(A-3)
O
O
O
Rh or Cu cat.
O
H
H
dihydrofuran: Theodorakis, 1999; furan: Reiser, 2005, enantioselective
B. Carbonylative oxaspirolactonization (our previous work, 2016)
Pd cat.
O
OH
O
O
O Pd
O
CO
Pd
O
HO
O
n
OH
n
Oxidant
n
n
2
5 (n = 1-3)
spiro-bicycles
3
4
C. Carbonylative fused lactonization (this work)
Pd cat.
CO
Pd
H
H
H
OH
R1
O
OH
H
R1
a
Our investigation started with known hydroxycyclo-
propanol 15a (Table 1).16 When it was subjected to the
carbonylative spirolactonization conditions we developed
before with ([Pd(neoc)(OAc)]2(OTf)2 as catalyst and 1,4-
benzoquinone (BQ) as oxidant,13 the formation of 16a
O
R1
O
R
R
Pd
R1
oxidant
O
O
O
O
OH
6
9
R
R
R
10
11
c
b
fused-bicycles
O
O
O
Pd
O
OH
R1
R1
O
+
O
was
not
observed
(entry
1).
Switching
R
OEt
R
R
R1
R1
[Pd(neoc)(OAc)]2(OTf)2 to palladium(II) trifluoroacetate
(Pd(TFA)2) was not fruitful either (entry 2). The break-
through came by using Cu(OTf)2 to replace BQ as the ox-
idant, which resulted in the formation of 16a in 6% yield
(entry 3). The structure of 16a was unambiguously con-
firmed by X-ray crystallographic analysis.17 The use of
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as
oxidant increased the yield to 18% (entry 4). Further in-
vestigation of palladium catalysts led to the identification
of Pd(OAc)2 as an optimal choice (entry 5-6). Other 1,4-
benzoquinone derivatives including 2,5-DMBQ and 2,6-
DMBQ were not effective (entry 8, 9). THF (entry 7),
O
7
8
12
14
O
O
13
Figure 2. Synthetic methodology design
We recently developed a Pd-catalyzed hydroxycyclo-
propanol ring opening carbonylative lactonization to syn-
thesize oxaspirolactones, another privileged scaffold fre-
quently appears in natural products (2®5, Figure 2B).13
This new synthetic capability significantly facilitated our
total syntheses of C12 oxygenated diterpenes and Stemona
alkaloids.14 With this success, we wondered the possibil-
ity of developing a catalytic carbonylation chemistry to
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Journal of the American Chemical Society
Pd(OAc)2 (10 mol%)
H
toluene (entry 10), and benzene (entry 14) were suitable
OH
R1
CO (balloon)
nH
R1
1
2
3
4
5
6
7
8
O
solvents with benzene giving slightly better yield (also
see 16e and 16n, Table 2). Elevating reaction temperature
(40 °C, entry 11) or increasing the amount of DDQ (entry
12) led to reduced reaction yield. Finally, reducing the re-
action concentration from 0.03 M to 0.01 M was benefi-
cial and product 16a was obtained in 74% yield (entry
14). The reaction is also scalable. Scaling up the reaction
from 0.2 mmol to 2.92 mmol led to the formation of 16a
in 65% yield. Moreover, when enantioenriched homoal-
lylic alcohol (1-phenylbut-3-en-1-ol, 92% ee) was used,
16a was obtained in 92% ee (73% yield) after a sequence
of cyclopropanol formation and carbonylative lactoniza-
tion. Given the ready availability of enantioenriched
homoallylic alcohols, our method offers an efficient
asymmetric alternative to THF-fused g-lactones.
O6 O 5
R
n
DDQ (2.0 equiv.)
benzene (0.01M), rt
aslow addition of DDQ; btoluene as solvent
R
OH
15 (n= 1-2)
16
H
H
H
H
O
O
O
O
O
Ph
O
O
Me
Me
16a: 74% (14 h)
x-ray of 16a
16b: 48% (7 h)
H
H
H
H
H
H
9
Me
O
F
O
OTs
O
O
O
O
Me
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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38
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40
41
42
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58
59
60
Me
Me
16c: 50%; 65%a (10 h)
16d: 44%; 62%a (10 h)
16e: 67%; 55%b (7 h)
H
H
H
H
H
H
O
O
O
N
O
O
O
Ts
O
O
Me
O
O
Me
Me
16f: 68% (7 h)
16g: 45% (7 h)
16h: 55% (7 h)
H
H
H
H
H
H
Table 1. Reaction condition optimizationa
O
N
O
O
O
O
O
Me
O
O
O
O
S
OTBS
Me
Me
H
Pd cat. (10 mol%)
CO (balloon)
OH
Ph
16i: 42% (4 h)
16j: 40% (7 h)
16k:36% (4 h)
O
Ph
Me
oxidant (2.0 equiv.)
solvent (M), CO (1 atm)
temp. (°C), 7 h
O
O
H
H
H
OH
Me
H
H
Me
Me
Me
Me
15a
O
O
16a
O
O
O
O
O
O
Me
OTBS
Me
Me
entry
reaction conditions
yieldb
16l: 65% (6 h)
16m: 55% (3 h)
16n: 57%; 46%b (5 h)
1
2
[Pd(neoc)(OAc)]2(OTf)2, BQ, DCE (0.03), rt
Pd(TFA)2, BQ, DCE (0.03), rt
0%
0%
H
H
H
Ph
O
O
O
3
4
5
Pd(TFA)2, Cu(OTf)2, DCE (0.03), rt
Pd(TFA)2, DDQ, DCE (0.03), rt
PdCl2, DDQ, DCE (0.03), rt
6%
18%
0%
O
O
Me
O
O
Me
O
O
Me
Ph
16o: 68% (3 h)
16p: 72% (4 h)
16q: 57% (17 h)
6
7
8
9
10
11
12
13
14
Pd(dppf)Cl2, DDQ, DCE (0.03), rt
Pd(OAc)2, DDQ, THF (0.03), rt
Pd(OAc)2, 2,5-DMBQ, THF (0.03), rt
Pd(OAc)2, 2,6-DMBQ, THF (0.03), rt
Pd(OAc)2, DDQ, toluene (0.03), rt
Pd(OAc)2, DDQ, toluene (0.03), 40 °C
Pd(OAc)2, DDQ (3.0 equiv.), toluene (0.03), rt
Pd(OAc)2, DDQ, toluene (0.01), rt
Pd(OAc)2, DDQ, benzene (0.01), rt
trace
58%
trace
trace
65%
51%
58%
70%
74%c,d
H
H
H
H
H
H
O
O
O
O
O
O
O
O
O
O
Me
OTBS
16r: 73% (6 h)
16s: 68% (6 h)
16t: 60% (5 h)
H
H
H
H
H
H
O
O
O
O
O
O
O
O
O
[a]General reaction conditions: To a stirred solution of 15a (1.0 equiv., 0.2
mmol) and DDQ (2.0 equiv.) in benzene (0.01 M) under carbon monoxide
(balloon) was added Pd(OAc)2 (0.1 equiv.) in one portion. The resulting
solution was stirred at room temperature until no more starting material left.
The reaction process was monitored by thin-layer chromatography; [b]Iso-
lated yield; [c]65% for 0.56-gram scale (2.92 mmol); [d] 73% yield and 92%
ee when 15a was prepared from the corresponding enantioenriched homoal-
lylic alcohol with 92% ee; 2,5-DMBQ: 2,5-dimethylbenzoquinone; 2,6-
DMBQ: 2,6-dimethylbenzoquinone.
H
Ph
Ph
16u: 60% (21 h)
16v: 65% (17 h)
16w: 65% (10 h)
H
H
H
H
H
O
O
O
O
O
O
O
O
Me
Me Me
Me Me
16x: 58% (4 h)
16y: 56% (30 h)
16za: 50% (5 h)
H
H
H
We then evaluated the scope and generality of this new
Pd-catalyzed hydroxycyclopropanol ring opening car-
bonylative lactonization. The reaction proved to be very
robust. A variety of hydroxycyclopropanol substrates
could be transformed into the corresponding cis-fused bi-
cyclic g-lactones. THF-fused g-lactone products with ei-
ther an aryl or an alkyl group at the C5-position could be
obtained. Notably, tosylate (16e), TBS-ether group (16k,
16l, 16s), and heteroaromatics including indole (16g), fu-
ran (16h), thiophene (16i), and pyrrole (16j) are all toler-
ated under the mild reaction conditions. Substrates con-
taining sterically hindered secondary (16m) and tertiary
alcohols (16n, 16o, 16p, 16q) were effective as well. Most
H
O
O
O
O
O
O
O
O
O
Me
Me
16zb: 48% (4 h)
Me
16zc: 53% (4 h)
16zd: 75% (4 h)
dr 1:1.3 (sm dr 1:1)
Table 2. Substrate scope
of the previously reported methods are limited to have hy-
drogen atom at C6 of the ring junction. In our case, the
substituent at this position can be altered from a methyl
group to a hydrogen (16w) or other bulkier alkyl groups
including cyclohexyl and isopropyl groups (16r, 16s, 16t,
16u, 16v, 16x, and 16y). Variation of the stereochemistry
of the secondary alcohol on the side chain was tolerated
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Journal of the American Chemical Society
Page 4 of 8
Me
1. Ti(Oi-Pr)4
O
as well (cf. 16x vs 16y). Similar reaction yields were ob-
tained, but the reaction of 16y took longer time. Further-
tol., rt to 40 o
C
O
OTBS
OH
1
2
3
4
5
6
7
8
O
Me
O
+
OTBS
OH
O
then c-C5H9MgCl
OH
25
OMe
THF, rt
more, THP-fused g-lactones could be produced in modest
to good yield (16za, 16zb, 16zc, and 16zd). Additionally,
slow addition of DDQ to the reaction mixture could be
beneficial to improve the reaction yield (cf. 16c and 16d),
but was not employed to all the substrates due to the op-
erational inconvenience.
23
24
15% (25% brsm)
TBSO
H
3. TsOH
acetone/H2O
50 oC, 6 h
O
2. Pd(OAc)2 (0.2 equiv.)
CO (balloon)
H
O
O
O
O
O
O
O
DDQ (1.8 equiv.)
benzene, rt, 8 h
42%
(99% brsm)
4. BzCl, pyr.
CH2Cl2, rt, 2 h
Me
O
O
O
H
Me
(±)-Paeonilide (1g)
O
H
Ph
O
O
57% (2 steps)
9
Pd(OAc)2 (10 mol%)
OH
Ph
O
26
HO
CO (balloon)
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
DDQ (2.0 equiv.)
benzene (0.01M)
rt, 5 h
OH
OH
Scheme 2. Total synthesis of (±)-paeonilide
Ph
OH
17
21: 47%
22: 0%
We next decided to test this new carbonylative lactoni-
zation method in natural product total synthesis and chose
paeonilide (1g) as our initial target. Paeonilide is a mon-
oterpenoid isolated from Paeonia delavayi by Liu and co-
workers.18 It selectively inhibits platelet aggregation in-
duced by platelet activating factor and has been previ-
ously synthesized by the groups of Zhang (chiral pool
synthesis starting from (R)-(-)-carvone, 14 LLS steps;19a
racemic, 17 LLS steps19b), Du (racemic, 6 LLS steps),19c
Reiser (enantioselective, 12 LLS steps),19d and Argade
(racemic, 11 LLS steps)19e from commercially available
starting materials. Our synthesis started with known com-
pounds 2320 and 24,21 which were prepared in one and
three steps, respectively, from commercially available
starting materials. They were united via a Kulinkovich re-
action to give desired hydroxycyclopropanol 25, albeit in
low yield due to the existence of the ketal, free alcohol,
and primary TBS ether. When 25 was subjected to the car-
bonylative lactonization conditions, bicyclic g-lactone 26
was produced in 42% yield (99% yield brsm). Removal
of the TBS and ketal protecting groups under acidic
H
O
Pd
O Pd
OH
PdII
O
H
Ph
OH
Ph
O
O
O
HO
O
20
Ph
19
18
OH
Scheme 1. A “competition” case
We also evaluated hydroxycyclopropanol 17, which
could undergo ring opening carbonylation to form either
fused g-lactone 21 or spirolactone 22 presumably via in-
termediate 19 or 20, respectively (Scheme 1). Both 19 and
20 could be derived from the same palladium-homoeno-
late 18. When 17 was subjected to the optimized car-
bonylative conditions (entry 14, Table 1), fused g-lactone
21 was obtained in 47% yield without any spirolactone 22
formation. Interestingly, even when the carbonylative spi-
rolactonization
conditions
were
used
([Pd(neoc)(OAc)]2(OTf)2 and BQ),13 fused lactone was
still the dominant product, but in lower yield.
Me2N
O
H
H
H
H
H
Ph
H
H
Ph
b. DIBAL-H
d. TFA
H
Ph
MeHNOC
HO
O
Ph
O
THF, -78 °C
80% (2 steps)
O
N
Me
O
O
O
DCM, rt
77% (2 steps)
O
O
Me
Me
28
Me
Me
29
27
30
a. tBuOCH(NMe2)2
c. MeNH2, THF, rt
90 °C
Me
Me
O
O
CO2H
S
N
Ph
H
HO
O
f.
Br
H
g. DIBAL-H
DCM, -78 °C
HO
H
O
H
H
e. LDA, THF
-78 °C
H
Ph
H
O
HN
Ph
Ph
O
O
Ph
O
O
Me
33
O
DMAP (cat.)
DCC, DCM
0 °C, 6 h
h. BF3•Et2O, Et3SiH
DCM, -78 °C
69%
PhCHO
82%
dr. 3:1
NH2
H
H
O
O
Me
Me
31
16a
Darunavir (34)
(HIV drug)
O
O
93%
i.
32
I
LDA
THF, -78 °C
82%
H
j. DIBAL-H, THF, -78 °C
k. OsO4, NaIO4, 2,6-lutidine, 0 °C
O
H
m. DIBAL-H, THF, -78 °C
n. OsO4, NaIO4, 2,6-lutidine, 0 °C
H
H
H
Ph
H
H
H
Ph
O
O
H
O
Ph
O
O
l. BF3•Et2O, Et3SiH, DCM, -78 °C
H
o. Jones oxidation, 0 °C to rt
O
Me
37
O
O
O
Me
36
68% (3 steps)
44% (3 steps)
Me
35
Scheme 3. Synthetic diversifications.
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Journal of the American Chemical Society
Weida Liang: 0000-0001-5205-0374
conditions followed by benzoate formation completed the
1
2
3
4
total synthesis (±)-paeonilide in 4 LLS steps in 3.6%
yield from known compounds 23 and 24 or 7 LLS steps
from commercially available starting materials.
Notes
The authors declare no competing financial interest.
Additionally, the fused bicyclic lactone product can be
diversified to other medicinally important structural scaf-
folds (Scheme 3). a-Methylene g-butyrolactone is an-
other privileged scaffold frequently found in natural prod-
ucts.22 Treatment of 16a with the Bredereck’s reagent fol-
lowed by DIBAL-H reduction23 could convert 16a to a-
methylene g-butyrolactone containing bicyclic product 28
in high yield. The lactone moiety of 16a could also be
converted to a lactam (cf. 30) via the treatment of MeNH2
followed by acid-promoted cyclization. Aldol reaction of
16a with benzaldehyde gave a 3:1 mixture of diastere-
omers in 82% yield. The relative stereochemistry of the
major product 31 was established by X-ray crystallo-
graphic analysis of its p-bromobenzoate derivative 32.17
Hexahydrofuro[2,3-b]furan is an important scaffold in
protease inhibitors, including the FDA-approved anti-
HIV drug Darunavir (34).24 Bicyclic lactone 16a could be
readily converted to hexahydrofuro[2,3-b]furan-contain-
ing product 33 via a sequential DIBAL-H and tri-
ethylsilane reduction process. Furthermore, 16a could
also be elaborated to tricyclic products 36 and 37 via a
series of standard functional group manipulations.25
These two tricyclic scaffolds have been found in natural
products such as gracilin B (1b) and potent protease in-
hibitors including GRL-0519A.26 These diversification
pathways demonstrate the potential broad application of
the newly developed carbonylative lactonization method.
ACKNOWLEDGMENT
5
6
7
8
This work was financially supported by NSF CAREER
Award 1553820. The NIH P30 CA023168 is acknowledged
for supporting shared NMR resources to Purdue Center for
Cancer Research. The XRD data is collected on a new single
crystal X-ray diffractometer supported by the NSF through
the Major Research Instrumentation Program under Grant
No. CHE 1625543.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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In summary, we have developed a novel Pd-catalyzed
hydroxycyclopropanol ring opening carbonylative lac-
tonization to synthesize THF/THP-fused bicyclic g-lac-
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental procedures and spectra data (PDF file)
Cystallographic data for 16a and 32 (cif file)
AUTHOR INFORMATION
Corresponding Author
* Email: mjdai@purdue.edu
ORCID
Mingji Dai: 0000-0001-7956-6426
Xinpei Cai: 0000-0002-2633-1882
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Table of Contents
1
2
3
4
5
Pd(OAc)2 (10 mol%)
H
OH
R1
nH
R1
CO (balloon)
O
n
R
DDQ (2.0 equiv.)
benzene, rt
O
O
OH
R
6
7
8
9
hydroxycyclopropanol
(n= 1-2)
fused bicyclic lactone
31 examples
36-75% yield
O
H
O
O
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(±)-Paeonilide
Me
8
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